Neurotransmitter serotonin or 5-Hydroxytryptamine (5-HT) is abundantly distributed in the central nervous system, including hippocampus and frontal cortex. The 5-HT receptors are a family of G-protein coupled receptors, characterized with 7-transmembrane helices and presently have fourteen known receptor subtypes, some of which exist as multiple splice variants [D. L. Murphy, A. M. Andrews, C. H. Wichems, Q. Li, M. Tohda and B. Greenberg, J. Clin. Psychiatry, 1998, 59 (suppl. 15), 4]. Serotonin (5-HT) influences a number of physiological functions and is implicated in a large number of central nervous system disorders, neurodegenerative diseases [W. E. Childers, Jr. and A. J. Robichaud, Ann. Rep. Med. Chem. 2005, 40, 17 herein incorporated by reference in its entirety] and other diseases.
One of the most actively studied 5-HT receptor subtypes is 5-HT1A, a 421 amino acid protein coded on human chromosome 5 by an intronless gene. 5-HT1A receptors are expressed in the central nervous system with highest density in the dorsal and median raphe nuclei as well as in the hippocampus. High density is also seen in the frontal cortex, entorhinal cortex, amygdale, and septum. 5-HT1A agonists and partial agonists have been implicated and have demonstrated effectiveness in the treatment of anxiety and depression in the clinic. Partial agonists of the 5-HT1A receptor mediate antidepressant activity through an increase in serotonergic neurotransmission. Although the mechanism of action is not yet fully understood, there is substantial evidence that the physiological and behavioral responses are achieved following desensitization of the 5-HT1A receptor-mediated response.
5-HT1A receptor partial agonists have been found to be useful in the treatment of various central nervous system diseases and disorders including anxiety, general anxiety disorders, depression, major depressive disorders, ADHD, ADD, schizophrenia, psychosis, panic disorders, social phobia, hot flashes associated with menopause, obesity, bulimia nervosa, anorexia nervosa, smoking cessation, schizophrenia, psychosis, sexual dysfunctions, premature ejaculation, memory and cognitive dysfunction, mild cognitive impairment associated with Alzheimer's diseases, Parkinson's diseases, Parkinson's disease psychosis, Huntington diseases and others.
According to the U.S. National Institute of Mental Health, generalized anxiety disorder and depression are the most prevalent mental illnesses. Most of the drugs used for treating anxiety and depression and stress related panic disorder suffer from troublesome side effects. Selective serotonin reuptake inhibitors (SSRIs) and the more recently developed serotonin nonadrenaline reuptake inhibitors (SNRIs) exert their effects by increasing neurotransmitter availability and transmission. Another class of drugs used for the short-term relief of anxiety is benzodiazepines. These sedating agents are controlled substances because of their addictive properties and can be lethal when used in combination with alcohol.
It is generally known that 5-HT1A receptor is involved in psychiatric disorders such as anxiety and depression (Fletcher, A.; Cliffe, I. A.; Dourish, C. T., Silent 5-HT1A receptor antagonists: utility as research tools and therapeutic agents. Trends Pharmacol. Sci. 1993, 14, 441-448, herein incorporated by reference; Hamon, M, Neuropharmacology of anxiety: perspective and prospects. Trends Pharmacol. Sci. 1994, 15, 36-39, herein incorporated by reference; Blier, P; Montigny, C.; Current advances and trends in the treatment of depression. Trends Pharmacol. Sci. 1994, 15, 220-226, herein incorporated by reference; Lo'pez-Rodriguez, M. L.; Rosado, M. L.; Benhamu, B; Morcillo, M. J; Sanz, A. M.; Orensanz, L.; Beneitez, M. E.; Fuentes, J. A.; Manzanares, J, Synthesis and structure activity relationships of a new model of arylpiperazines. 1.2-[[4-(o-Methoxyphenyl)piperazin-1-yl]methyl]-1,3-dioxoperhydromidazo[1,5-a]pyridine: A selective 5-HT1A receptor agonist. J. Med. Chem. 1996, 39, 4439-4450, herein incorporated by reference; Becker, O M.; Dhanoa, D S.; Marantz, Y,; Chen, D.; Shacham, S.; Cheruku, S.; Heifetz, A.; Mohanty, P.; Fichman, M.; Sharadendu, A.; Nudelman, R.; Kauffman, M; Noiman, S. An integrated in silico 3D model-driven discovery of a novel, potent and selective Amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression. J. Med. Chem. 2006, 49, 3116-3135, herein incorporated by reference). Buspirone, an arylpiperazine that has shown high affinity for the 5-HT1A receptor, was the first drug to be approved for clinical use for the treatment of anxiety and depression (Taylor, D P.; Moon, S. L. Buspirone and related compounds as alternative anxiolytics. Neuropeptides 1991, 19, 15-19; Levy, A. D.; van der Kar, L. D.; Endocrine and receptor pharmacology of serotoninergic anxiolytics, antipsychotics and antidepressants. Life Sci. 1992, 51, 83-94). However, buspirone has poor receptor selectivity, poor oral bioavailability, duration of action, and slow onset. Buspirone has high affinity for alpha-1 (Raghupathi, R. K.; Rydelek-Fitzgerald, L.; Teitler, M; Glennon, R. A. Analogs of the 5-HT1A serotonin antagonist 1-(2-Methoxyphenyl)-4-[4-(2-phthalimidobutyl)piperazine] with reduced alpha-1 adrenergic affinity. J. Med. Chem. 1991, 34, 2633-2638). The high affinity of buspirone for the alpha-1 adrenergic receptor is attributable to its adverse effect of orthostatic hypotension (decreased blood pressure).
Effects of a 5-HT1A partial agonist PRX-00023 on anxiety and depression including general anxiety disorders and major depressive disorders from a randomized, double-blind, placebo controlled trial conducted in 311 subjects have shown significant potential for the treatment of general anxiety disorders and major depressive disorders and with fewer side effects (Rickels, K.; Mathew S.; Banov, M. D; Zimbroff, D. L.; Oshana, S.; Parsons, E. C. Jr.; Donahue, S. R.; Kauffman, M.; Iyer, G. R.; Reinhard, J. F. Jr., J. Clin. Psychopharmacol. 2008, 28(2), 235-9, herein incorporated by reference).
Serotonin or 5-Hydroxytryptamine receptor subtype 1A (5-HT1A) offers a valuable and efficacious therapeutic approach to the treatment of anxiety and major depression (Blier, P.; Ward, N. M. Is there a role for 5-HT1A agonists in the treatment of depression. Biol. Psychiatry. 2003, 53(3), 193-203, herein incorporated by reference).
Vilazodone was approved for the treatment of major depressive disorder by the US FDA in 2011 (Ann. Rep. Med. Chem. 2012, 47, 558; Frampton, J E., CNS Drugs 2011, 25, 615; Laughren, T. P. et. al. J. Clin. Psychiatry 2011, 72, 1166, herein incorporated by reference). Major depressive disorder (MDD) is characterized by persistent low mood, sadness, loss of interest in previously enjoyed activities, feelings of guilt or worthlessness, and thoughts of death or suicide. Nearly 15% of the United States population will experience MDD in their lifetime, with more prevalence in women. Vilazodone (Viibryd) is a 5-HT1A partial agonist and dual serotonin reuptake inhibitor. Vilazodone is a novel antidepressant that combines potent serotonin reuptake inhibition (IC50=0.2 nM) with high affinity for 5-HT1A receptor (IC50=0.5 nM) and partial agonist functional activity for 5-HT1A receptor. Vilazodone demonstrated efficacy in preclinical rat and mice models of depression (Page, M. E.; Cryan, J. F.; Sullivan, A.; Dalvi, A; Saucy, B.; Manning, D. R.; Lucki, I. J. Pharmacol. Exp. Ther. 2002, 302, 1220). As with all approved antidepressant drugs in the United States, vilazodone has a black box warning describing the increased risk of suicidal thinking and behavior in children, adolescents, and young adults.
Current antidepressants including selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors and tricyclic antidepressants-all modulate monoamine levels and have limitations that include a lack of effectiveness in a substantial proportion of patients. Nearly 50% of patients have depression that is difficult to treat and need drugs with new modes of action. New antidepressants that target the kappa-opioid receptor could be valuable for patients suffering from stress-induced component in their illness. Patients with anxiety and depression have heightened sensitivities to stress exposure, and the endogenous dynorphin opioid peptides that are released during stress act at kappa-opioid receptors. In preclinical models, kappa-opioid receptor antagonists effectively reduce the anxiety-like and depression-like behaviors caused by stress exposure.
Recently, a clinical candidate ALKS-5461, a combination therapy composed of a selective mu-opioid receptor antagonist, samidorphan (ALKS33), and a mixed kappa-opioid receptor antagonist and a mu-opiod receptor agonist, buprenorphine (that is already approved for the treatment of pain and opioid addiction), have shown positive results in Phase 2 clinical trials (ClinicalTrials.gov Identifier NCT01500200) for the treatment of patients with major depressive disorders (MDD) (http://clinicaltrials.gov/ct2/show/NCT01500200) who do not respond to current therapies. Buprenorphine has weak mu-opiod receptor (where morphine and oxycodone act) agonist activity, there are risks of sedation and addiction. So combination of buprenorphine with a mu-opioid antagonist offers the formulation superior functional selectivity.
The compounds of the present invention of formula 1 have been found to be potent 5-HT1A partial agonists and offer a novel, safer and effective treatment when administered alone or in combination with existing or new therapies such as vilazodone and ALKS-5461 respectively for the treatment of anxiety, depression and related major depressive disorders.
As can be seen from the package insert of the atypical antipsychotic drug, Aripiperazole (Abilify), it has been approved as a tablet, oral formulation and as an injectable agent by the US. FDA for the use of various central nervous system diseases and disorders including schizophrenia, acute treatment of manic or mixed episodes associated with bipolar I disorder as monotherapy or as an adjunct lithium or valproate, maintenance treatment of bipolar I disorder both as monotherapy or as an adjunct lithium or valproate, adjunctive treatment of major depressive disorders (MDD), treatment of irritability associated with autistic disorder, acute treatment of agitation associated with schizophrenia or bipolar I disorder (intramuscular injection) or bipolar mania.
Aripiprazole has been shown to have partial agonist functional activity at 5-HT1A receptor with binding affinity (Ki) of 5.6 nM and varied biological activity at other 5-HT receptor subtype including Ki of 832 nM for 5-HT1B receptor, Ki of 65 nM for 5-HT1D, Ki of 8.7 nM for 5-HT2A receptor, Ki of 0.36 nM at 5-HT2B receptor, Ki of 22.4 nM at 5-HT2C receptor, Ki of 628 nM at 5-HT3, Ki of 1240 nM at 5-HT5A receptor, and Ki of 642 nM at 5-HT6 receptor. Aripiperazole also shows varied degree of activity for dopamine receptors, D1 receptor Ki of 1170 nM, D2 receptor Ki of 1.6 nM and acts as partial agonist, D3 receptor Ki of 5.4 nM, D4 receptor Ki of 514 nM and D5 receptor Ki of 2130 nM. Aripiperazole has a warning of increased risk of suicidal thoughts and behavior, and early patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
Lurasidone, an atypical antipsychotic agent, was approved in the United States in 2010 for the treatment of schizophrenia (Ann. Rep. Med. Chem. 2011, 46, 473; Hopkins, C. R. ACS Chem. Neurosci. 2011, 2, 58; Citrome, L. Int. J. Clin. Prac. 2011, 65, 189). Lurasidone has high affinity for 5-HT1A receptor (IC50 6 nM), dopamine D2 receptor (Ki 2 nM) and 5-HT2A (IC50=2 nM) (Ishibashi, T. et. al. J. Pharmacol. Exp Ther. 2010, 334, 171). Lurasidone is also a partial agonist at 5-HT1A receptor which produces beneficial cognitive properties. Lurasidone has shown efficacy in preclinical behavioral model of psychosis, depression and anxiety. Lurasidone also has a black box warning for increased mortality in elderly patients with dementia-related psychosis. Schizophrenia is a debilitating mental disorder that affects 1% of the population worldwide.
5-HT1A partial agonists have been shown to have activity for the treatment of Attention deficit hyperactivity disorder (ADHD) particularly in combination with norepinephrine reuptake inhibitors (Gray, D. L.; Xu, W.; Campbell, B. M; Dounay, A. B.; Barta, N.; Boroski, S.; Denny, L.; Evans, L.; Stratman, N.; Probert, Al. Discovery and pharmacological characterization of arylpiperazine and piperadine ethers as dual acting norepinephrine reuptake inhibitors and 5-HT1A partial agonists. Bioorg. Med. Chem. Lett. 2009, 19 (23), 6604-6607, herein incorporated by reference).
Since the FDA approval of buspirone for the treatment of generalized anxiety disorders (GAD), numerous studies have examined the safety and efficacy of buspirone for patients with not only generalized feeling of anxiety, but also panic disorder, major depressive disorder, obsessive-compulsive disorder, body dysmorphic disorder, social phobia, post-traumatic stress disorder, SSRI-induced adverse events, dementia, behavioural disturbances, attention deficit-hyperactivity disorder (ADHD), and tobacco dependency. Apter and Allen reviews the growing body of research relating to new therapeutic uses of buspirone (Apter, J. F.; Allen, L. A. Buspirone: Future directions. J. Clin. Psychopharmacol. 1999, 19:86-93).
The 5-HT1A agonists are potentially safer and more effective therapeutic drugs for the treatment of anxiety disorders including, General Anxiety Disorder (GAD), Panic Disorder (PD), Post-Traumatic Stress Disorder (PTSD), Social Phobia (SP), Health Anxiety (Hypochondriasis), depression, major depressive disorders, unipolar depression, bipolar I depression disorder, bipolar II depression disorder, treatment-resistant depression, single episodic and recurrent major depressive disorders, depression in the medically ill, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), Obsessive-Compulsive Disorder (OCD), Obsessive-Compulsive Personality Disorder (OCPD), Autism Spectrum Disorder (ASD), schizophrenia, psychosis, epilepsy, seizures, hot flashes due to menopause, age-related macular degeneration (AMD), premature ejaculation, male erectile dysfunction, sexual dysfunction, obesity, eating disorders, bulimia nervosa, anorexia nervosa, angina, smoking cessation, migraine, pain, nociception, sleep disorders, autism, Rett's syndrome, cyclothymic disorder, neural injury, neurodegenerative diseases, Parkinson's disease, Parkinson's disease psychosis, Huntington disease, Alzheimer's disease, frontotemporal dementia, cognitive impairment associated with age-related dementia, Alzheimer's disease, schizophrenia, psychosis, depression, surgery or any medical illness.
The 5-HT1A receptors have also been implicated in the pathophysiology of age-related macular degeneration (AMD), epilepsy and seizures and other neurodegeneration diseases and disorders. 5-HT1A receptor modulators (agonist or partial agonist) have shown potential for the treatment of age-related macular degeneration (AMD), epilepsy, seizures, premature ejaculation, obesity, Parkinsons' disease, psychosis and other central nervous system diseases mentioned below.
The 5-HT1A (5-hydroxytryptamine or serotonin) receptor agonists, partial agonists or antagonists are neuroprotective agents. 5-HT1A agonists have been shown to be neuroprotective agents against excitotoxic neuronal damage in animal models of central nervous system injury such as stroke and traumatic brain injury (Mauler, F.; Horvath, E., J. Cereb. Blood Flow Metab. 2005, 25, 451-45; Ramos, A. J., The 5-HT1A receptor agonist, 8-OH-DPAT, protects neurons and reduces astroglial reaction after ischemic damage caused by cortical devascularization. Brain Res. 2004, 1030, 201-220, herein incorporated by reference). Several putative mechanisms that have been proposed include inhibition of caspase 3 and activation of the mitogen-activated protein kinase (MAPK) signaling pathway (Adayev et. al., Biochim. Biophys. Acta., 2003, 1640, 85-96) which results in increased expression of anti-apoptotic proteins (e.g., XIAP, BCL-2, and BCL-XL) (Hsiung et. al., J. Neurochem., 2005, 95, 1653-1666).
As is shown by Collier et. al. from Alcon (Collier et al. Investigative Ophthalmology & Visual Science, (IOVS), 2011, 52 (5), 2118-2126, herein incorporated by reference) the 5-HT1A receptor agonist may offer a novel approach to retinal neuroprotection for retinal disorders such as age-related macular degeneration (AMD). Oxidative stress and inflammation are thought to play pivotal roles in the etiology of age-related macular degeneration (Kanda et. al. Br. J. Ophthalmol. 2008, 92, 448-450; Beatty et. al. Surv. Ophthalmol. 2000, 45, 115-134; Winkler et. al. Mol. Vis. 1999, 5, 32-42); Shen et. al. Histol. Histopathol. 2007, 22, 1301-1308, herein incorporated by reference). Topical ocular application with 1.75% of the 5-HT1A agonist AL-8309B once or twice daily provided protection from photo-oxidative damage to the retina (Collier et al). This is a very useful, convenient and less painful route of administration for the potential treatment of retinal disorders such as macular degeneration. The current available treatments require injection of VEGF inhibitors directly into the eye, every four to six weeks. A clinical trial evaluating the safety and efficacy of topically administered 5-HT1A partial agonist, AL-8309B, for the treatment of advanced nonexudative age-related macular degeneration (geographic atrophy) is under way (Geographic atrophy treatment evaluation. ClinicalTrials.gov Identifier: NCT00890097).
In addition, the 5-HT1A receptor has been implicated in the pathophysiology of epilepsy. The neurotransmitter 5-HT (serotonin) assists communication of nerve cells. Previous research studies have shown that 5-HT activity may be diminished in the CNS areas of the brain where seizures occur. Research studies also suggest that increase in activity at the 5-HT receptor site on the nerve cells may help prevent seizures. The 5-HT agonists such as 5-HT1A receptor agonists or partial agonists may reduce epileptic seizures. A 5-HT1A partial agonist PRX-00023 (Becker, O M.; Dhanoa, D S.; Marantz, Y,; Chen, D.; Shacham, S.; Cheruku, S.; Heifetz, A.; Mohanty, P.; Fichman, M.; Sharadendu, A.; Nudelman, R.; Kauffman, M; Noiman, S. An integrated in silico 3D model-driven discovery of a novel, potent and selective Amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression. J. Med. Chem. 2006, 49, 3116-3135, herein incorporated by reference), is undergoing Phase II clinical trials for the treatment of epilepsy specifically localization-related epilepsy (http://clinicaltrials.gov/ct2/show/NCT01281956).
The 5-HT1A receptors have also been implicated in the pathophysiology underlying premature ejaculation. It may also have a direct or indirect role in other sexual dysfunction such as erectile dysfunction or sexual desire. Premature ejaculation (PE) is the most common form of male sexual dysfunction affecting nearly 40% of men globally. Premature ejaculation (PE) is a common sexual dysfunction in men that is characterized by a short time to ejaculation and a lack of control over ejaculation. PE is associated with distress for men and their partners. Lack of knowledge about the etiology of PE and lack of approved treatments might contribute to its under-diagnosis and under-treatment. Ejaculation is a reflux comprising different sensory pathways, motor centers, and nerve pathways regulated by serotonin and dopamine. The pathophysiology of PE includes decreased serotonin neurotransmission and 5-HT1A receptor hypersenstivity. Selective serotonin reuptake inhibitors (SSRIs) commonly used as antidepressants are often used to treat PE because of their frequent side effect delayed ejaculation. Animal studies have shown that SSRIs block presynaptic membranes of 5-HT transporters, resulting in higher serotonin (5-HT) levels in the synaptic cleft. The 5-HT then binds to 5-HT1A receptor and 5-HT2C to delay ejaculation. The most commonly used SSRIs to treat PE include the long-acting agents, fluoxetine, paroxetine, sertraline, and citalopram. Several clinical studies have shown that chronic use of SSRIs results in prolonged intravaginal ejaculatory latency time in men with PE. However, chronic use of SSRIs is associated with undesirable sexual side effects and withdrawal symptoms upon discontinuation. Dapoxetine hydrochloride is the recent serotonin modulator approved in 2011 by the US FDA for the oral on-demand treatment of PE in men between 18-64 years of age. Dapoxetine HCl is a short-acting SSRI. It is differentiated from the existing SSRI treatments for PE because it can be dosed on an as-needed basis (Ann. Rep. Med. Chem. 2010, 45, 488; Sorbera, L. A., et. al. Drugs Future 2004, 29, 1201; Hellstrom, W. J. G. et. al. Neuropsychiatr. Dis. Treat., 2009, 5, 37, herein incorporated by reference). The most common adverse events with dapoxetine included nausea, diarrhea, headache, dizziness, and somnolence.
The organic factors involved in PE are not well understood but serotonin (5-hydroxytryptamine, 5-HT) is important at the level of the central nervous system in the complex regulatory mechanisms involved in ejaculation. Current available medicines for PE in addition to off-label use of SSRIs are PDE-5 inhibitors and topical anaesthetics, which have shown variable efficacy and tolerability. Drugs for treating PE will continue to develop as the understanding of ejaculation expands, including the role of central neurotransmitters as future targets to delay ejaculation. The neurotransmitter 5-HT appears to be a key mediator in the neurophysiology of ejaculation (Giuliano et al. Eur. Urol. 2005, 48, 408-417). 5-HT neurons express somatodendritic autoreceptors (including 5-HT1A receptors present in the mesencephalic and medullary raphe nuclei), presynaptic autoreceptors (5-HT1B and 5-HT1D), 5-HT signalling receptors (e.g. 5-HT2C), and 5-HT reuptake transporters, each of which mediate different effects on cellular activation and 5-HT signaling Waldinger et al. Behav. Brain Res. 1998, 92, 111). In general, activation of 5-HT1A autoreceptors decreases 5-HT release by the pre-synaptic neurone, providing a negative-feedback mechanism for 5-HT neurotransmission (Giouliano et al. Eur. Urol. 2006, 50, 454-66). Signal transduction through 5-HT1A and 5-HT2C receptors plays a key role in regulating ejaculation at the central level (Ahlenius, et. al. Neurochem Res. 1997, 22, 1065-70). Activation of postsynaptic 5-HT2C or 5-HT1B receptors prolongs ejaculatory latency, whereas activation of presynaptic 5-HT1A autoreceptors, which inhibits 5-HT release, decreases ejaculatory latency. It was suggested that PE might be associated with the presence of low synaptic levels of 5-HT in regions of the CNS that modulate ejaculation, possibly because of variations in 5-HT receptor sensitivity. It seems that increasing central 5-HT is a relevant pharmacological approach to treat premature ejaculation (PE).
5-HT1A receptors play important role in Parkinson's disease and schizophrenia. Specifically, 5-HT1A receptors seem to be a promising target for alleviating antipsychotic-induced extrapyramidal side effects (EPS) and cognitive/affective disorders in schizophrenia. In the treatment of patients with Parkinson's disease, 5-HT1A agonists are expected to improve not only affective symptoms (e.g., anxiety and depression), but also the core parkinsonian symptoms as well as antiparkinsonian agents-induced side effects (e.g., L-DOPA-induced dyskinesia). The review of therapeutic mechanisms mediated by 5-HT1A receptors in schizophrenia and Parkinson's disease are reported (Ohno et al. CNS Neuroscience and Therapeutics, 2011, 17 (1), 58-65, herein incorporated by reference). There is a potential promising use of new 5-HT1A agonists in the treatment of Parkinson's disease, schizophrenia and psychosis related to these brain disorders.
5-HT1A receptor agonists have also been implicated in the treatment of obesity and related eating disorders such as bulimia nervosa and anorexia nervosa. Peripheral injection of serotonin reduces food intake and specifically decreases fat intake. Since the majority of serotonin (5-HT) is present in the gastrointestinal tract, it is highly likely that 5-HT receptors in this tissue play an important role in the regulation of food intake in response to enteral signals or to the rate of gastric emptying.
Belviq (Lorcaserin HCl) has recently been approved by the U.S FDA for the treatment of obesity and controlling eating and/or food intake. As is clear from its package insert, Belviq decreases food consumption and promotes satiety by activating 5-HT2C receptor in the brain. Activation of 5-HT receptors may help overweight or obese patients eat less and feel full. The exact mechanism of action is not clear.
As seen from its package insert Qsymia® (phentermine and topiramate) has been approved by the U.S. FDA in 2012 for treatment of obesity. Qsymia is a combination of phentermine, a sympathomimetic amine anorectic, and topiramate extended-release form, an antiepileptic drug approved as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adults. Phentermine releases serotonin (5-HT), dopamine and norepinephrine at clinically relevant doses (Rothman, R. B., et. al. Synapse, 2001, 39 (1), 32-4). Phentermine acts on the hypothalamus to stimulate the release of norepinephrine that signal reduction in appetite.
Contrave has completed pivotal clinical trials (Phase III) for the treatment of obesity and a New Drug Application has been submitted and has been reviewed by the U.S. FDA (http://www.orexigen.com/about-orexigen.html). Contrave is a combination of bupropion and naltrexone. Bupropion increases the dopamine activity in the brain which leads to reduction in appetite and increase in energy expenditure by enhancing neuron activity. Bupropion is a norepinephrine and dopamine reuptake inhibitor. Naltrexone on the other hand is an opioid receptor antagonist and prevents the feedback inhibition of neurons. Thus, Contrave may regulate activity in the dopamine reward system of the brain which helps control food cravings, overeating behaviors and increase metabolism.
The 5-HT1A receptors in medial prefrontal cortex (mPFC) are involved in the modulation of dopaminergic activity (Diaz-Mataix, L.; Scorza, M. C.; Borotolozzi, A.; Toth, M.; Celada, P.; Artigas, F. The Journal of Neuroscience, 2005, 25(47), 10831-10843). The results published in this paper showed that the activation of medial prefrontal cortex (mPFC) enhances the activity of ventral tegmental area (VTA) DA neurons and mesocortical dopamine release. The highly selective 5-HT1A agonist BAYx3702 was found to increase the firing rate and burst firing of dopamine (DA) neurons in the ventral tegmental area (VTA) and DA release in the VTA and mPFC. The increase in DA release in both areas was potentiated by nomifensine coperfusion. The application of BAY in rat and mouse mPFC by reverse dialysis increased local extracellular DA at a low concentration of 3 micromolar and reduced it at a higher concentration (30 micromolar). Both effects disappeared in a 5-HT1A knock-out mice.
Buspirone (Buspar), a 5-HT1A partial agonist has been tested clinically for smoking cessation. Early open-label studies suggested that buspirone increased quit rates and reduced withdrawal symptoms (Hilleman D. E.; Mohiuddin, S. M; Del Corte, M. G.; Sketch, M. H. Sr., Effect of buspirone on withdrawal symptoms associated with smoking cessation. Arch. Intern. Med. 1992, 152 (2), 350-352; Robinson, M. D.; Smith, W. A.; Cederstrom, E. A.; Sutherland, D. E.; Buspirone effect on tobacco withdrawal symptoms: a pilot study. J. Am. Board Fam. Pract., 1991, 4(2), 89-94; West, R.; Hajek, P.; McNeill, A. Effect of buspirone on cigarette withdrawal symptoms and short term abstinence rates in a smoker's clinic. Psychopharmacology, 1991, 104 (1), 91-96).
In addition, as seen from its package insert, Zyban® (bupropion hydrochloride) has been approved by the U.S. FDA for use in smoking cessation programs. Bupropion HCl is a 5HT1A partial agonist as shown by Mansari et al. (El Mansari, M.; Ghanbari, R.; Janssen, S.; Blier, P., Sustained administration of bupropion alters the neuronal activity of serotonin, norepinephrine but not dopamine neurons in the rat brain. Neuropharmacology, 2008, 55 (7), 1191-98).
Hot flashes associated with menopause occur in up to 75% of women and can persist up to five years, or even longer in some women. Hot flashes are not life threatening but the symptoms can be very bothersome, causing discomfort, embarrassment and disruption of sleep. The U.S. FDA has approved the antidepressant paroxetine for the treatment of moderate to severe hot flashes (vasomotor symptoms) associated with menopause (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm359030.htm). Paroxetine mesylate (trade name: Brisdelle), a selective serotonin reuptake inhibitor (SSRI), is currently the only non-hormonal treatment for hot flashes approved by the FDA. There are various FDA-approved treatments for hot flashes but all contain either estrogen alone or estrogen plus a projestin. The mechanism by paroxetine (Brisdelle) reduces hot flashes is unknown. The most common side effect in patients treated with paroxetine were headache, fatigue and nausea/vomiting. All antidepressant agents including paroxetine have a boxed warning about an increased risk of suicide in children and young adults. Of particular concern to menopause women is the potential for weight gain and sexual dysfunction, which are adverse effects associated with SSRI and SNRIs. Paroxetine also has activity at the 5-HT1A and other 5-HT receptors and therefore, potent and selective 5-HT1A partial agonist will offer a significant advantage over current therapies including paroxetine.
Trazodone, a 5-HT1A partial agonist approved for the treatment of anxiety (Haria, M., et al. Trazadone. A review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders. Drugs Aging, 1994, 4, 331-55), is also used for the treatment of insomnia (Nierenberg, A. A., et al. Trazodone for antidepressant-associated insomnia, Am J. Psychiatry, 1994, 151, 1069-72); Kaynak, H. et al. The effects of Trazodone on sleep in patients treated with stimulant antidepressants., Sleep Med. 2004, 5, 15-20), Fibromyalgia (Morillas-Arques, P., et. al. Trazodone for the treatment of fibromyalgia: an open label, 12 week study, BMC Musculoskeletal Disorders, 2010, 11, 204, http://www.biomedcentral.com/1471-2474/11/204) and alcohol withdrawal. Borras, L; de Tamary, P.; Constant, E-L.; Huguelet, P.; Eytan, A. Successful treatment of alcohol withdrawal with Trazodone. Pharmacopsychiatry, 2006, 39 (6), 232).